tbuckley/cabot-search huggingface dataset:
Abstract 3783: Role of microRNA 28-3p in prostate cancer progression
Authors: Amritha Sreekumar, Sharanjot Saini
Journal: Cancer Research (2023)

Abstract Prostate cancer (PCa) is a leading cause of cancer incidence and mortality among men. Prostate cancer is driven by androgens acting via androgen receptor (AR). Therefore, this cancer is treated with androgen deprivation therapy (ADT) initially. However, the cancer rapidly evolves to be resistant to ADT and progresses to a more invasive stage referred to as ‘Castration Resistant prostate cancer’ (CRPC). CRPC is treated with second generation of AR pathway inhibitors such as Enzalutamide and Abiraterone. These treatments are effective initially. However, drug resistance develops in a significant fraction of patients and the cancer undergoes ‘neuroendocrine trans-differentiation (NED) to a lethal variant called ‘neuroendocrine prostate cancer’ (NEPC). As a result of NED, PCa cells express neuronal markers such as synaptophysin, chromogranin A and enolase. The molecular basis of NED is not yet fully defined. With a focus on identifying the role of microRNAs (miRNAs) in NEPC, we performed small RNA sequencing in CRPC tumors with and without NED. This sequencing identified miR-28-3p to be significantly downregulated in CRPC-NE samples as compared to CRPC-adenocarcinomas (CRPC-Adeno). In view of this, we examined the role of this miRNA in NEPC. Analyses of TCGA data of prostate adenocarcinomas suggest that miR 28-3p has an oncogenic role in primary prostate tumors. However, its expression declines in tumors with increasing Gleason score. We profiled the expression of miR-28-3p in patient-derived xenograft models and clinical CRPC-NE and CRPC-Adeno tissues by real time PCR. Our profiling showed a trend towards downregulation with increased NED. Basal expression of miR 28-3p in various prostate cancer cell lines showed an elevated level in androgen dependent cell lines whereas significantly less expression in NEPC cell lines, LASCPC-01 and NCI-H660. In this study, we generated PC3 cell line that stably expresses miR-28 for understanding its functional role in regulating PCa. Preliminary functional assays including cell viability assay, cell cycle studies and invasion and migration assay suggest a tumor suppressor role of miR-28-3p in advanced prostate cancer. In conclusion, our data shows that miR 28-3p potentially has a biphasic role in PCa, where it is oncogenic in early stages and acts as a tumor suppressor in late stage PCa. Citation Format: Amritha Sreekumar, Sharanjot Saini. Role of microRNA 28-3p in prostate cancer progression. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3783.
Abstract 378: Ferritin regulates oxaliplatin sensitivity and immunosuppression in pancreatic ductal adenocarcinoma
Authors: Ching-Feng Chiu
Journal: Cancer Research (2023)

Abstract Oxaliplatin, a third-generation of platinum analog, has been used for the treatment of colorectal, gastric, and advanced pancreatic ductal adenocarcinoma (PDAC); however, its relatively high toxicity reduced its efficacy in clinical use. Recently, we found that organic cation transporter 2 (OCT2) expression is positively correlated to Oxaliplatin sensitivity in PDAC cells and better survival outcomes in PDAC patients with chemotherapy, suggesting that OCT2 level is important not only in predicting sensitivity to oxaliplatin but also in guiding dose adjustments to minimize toxicity. Here, we observed the significance of serum Ferritin as a prognostic marker for pancreatic cancer, and further identified Ferritin heavy chain (FTH1) down-regulated OCT2 level and reduced Oxaliplatin sensitivity of advanced PDAC cells in vitro and in vivo. Our study reveals the negative correlation between FTH1 and OCT2 levels in PDAC database analysis and reducing FTH1 expression with Deferasirox (DFX), which is an agent that has been widely used for patients with iron overload, reversed OCT2 expression and Oxaliplatin sensitization in metastatic PDAC cells. Additionally, we identified that exosomal Ferritin/FTH1 from PDAC cells may enhance M1-type to M2-type macrophage polarization to build up immunosuppression in the tumor microenvironment. Citation Format: Ching-Feng Chiu. Ferritin regulates oxaliplatin sensitivity and immunosuppression in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 378.
Abstract 1190: Mimicking CAFs, pial cells support leptomeningeal metastasis
Authors: Jenna Snyder, Jan Remsik, Nicholas Prescott, Adrienne Boire
Journal: Cancer Research (2023)

Abstract Leptomeningeal metastasis (LM), the spread of cancer into cerebrospinal fluid (CSF)-filled coverings of the brain and spinal cord, is a dismal complication of cancer leading to rapid neurologic disability and death. While a diverse array of primary tumors may result in LM, recent work from our laboratory (Chi Y et al 2020 Science) demonstrates a conserved transcriptional signature, independent of primary tumor, suggesting that tumor-microenvironmental interactions play a dominant role in this pathology. We have proteomically interrogated CSF collected from breast (n = 45), lung (n = 30), and melanoma (n = 27) patients with and without LM. We detect robust expression of inflammatory cytokines in all LM+ samples, 15 of these cytokines including IL8, IL6, and CXCL1 are conserved across tumor types in the presence of LM. Because cancer cells in the CSF do not express mRNA associated with these cytokines, we hypothesized that these inflammatory cytokines may originate from the microenvironment. Within the leptomeninges, LM cells adhere to and interact with the innermost layer of the meninges, the pia mater, which contains fibroblast-like cells. Co-culture of cancer cells with pial cells induced changes in the pial cell transcriptome and secretome, leading to increased IL8, IL6, and CXCL1 production. This communication between cancer cells and pial cells is preserved in the absence of direct cell-cell contact. To identify cancer cell signal(s) responsible for these pial cell changes, we subjected cancer cell conditioned media to gel filtration, and uncovered TGFBI as a key secreted factor inducing pial cell transcriptional changes. These pial cells support cancer cell growth in vivo, as measured by co-implantation experiments. In autopsy samples, we detect IL8, IL6, and CXCL1 expression in the pia of patients harboring LM. Taken together, these observations support a cancer-associated-fibroblast like role for pial cells in the setting of LM. We are currently carrying out single cell RNA sequencing of both human and mouse LM samples to capture heterogeneity in both cancer and pial cell responses, and to place these cells in the larger context of the CAF knowledgebase. Our work extends the CAF phenotype beyond classical fibroblasts to include pial cells, suggesting novel therapeutic opportunities within CNS malignancies. Citation Format: Jenna Snyder, Jan Remsik, Nicholas Prescott, Adrienne Boire. Mimicking CAFs, pial cells support leptomeningeal metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1190.
Abstract 4899: Inhibition of murine tumor growth by decitabine is correlated with enhanced expression of the mouse mammary tumor virus
Authors: Jieyu Zhang, Savannah Higgins, Riley Smith, Tania Reginald, Andrew Qi, Jiayi Li, Anna King, Yingguang Liu
Journal: Cancer Research (2023)

Abstract The purpose of this study is to clarify the mechanisms of the antineoplastic effect of decitabine (DAC), a DNA methyltransferase inhibitor. We previously reported that DAC inhibited the proliferation of the 4T1 mammary cancer cell line in vitro while inhibiting MMTV env and pol expression in the same cells. Here we present findings in vivo using two murine tumor models. We inoculated 4T1 cells into BALB/c mice from which the cell line was derived. In addition, we inoculated the murine colon carcinoma cell line, MC38, into C57BL/6 mice, the mouse strain of its origin. We treated the mice with DAC when tumors became palpable. DAC inhibited tumor growth in both tumor models and inhibited metastasis of 4T1 cells into the lungs. Quantitative PCR detected elevated expression of MMTV genes in the tumor tissues of DAC-treated mice in both models. The levels of MMTV env RNA in tumor tissues were negatively correlated with tumor mass in both models, so were the levels of the MMTV Env protein in 4T1 tumors. DAC also significantly mitigated tumor-induced splenomegaly. Hepatotoxicity of DAC was observed in C57BL/6 mice. Our data suggest the possibility that decitabine inhibits tumor growth in vivo and in vitro via different mechanisms. The findings also support the current understanding of decitabine upregulating endogenous retroviruses (ERVs) which subsequently activate an interferon response. The negative correlation between tumor mass and MMTV Env protein expression suggests a possible role of ERV proteins serving as tumor-associated antigens and decitabine enhancing adaptive immunity against cancer by stimulating ERV expression on tumor cells. Further studies of the interaction between decitabine and MMTV using immunodeficient mice may help us understand the possible involvement of adaptive immunity in the pharmacodynamics of decitabine as well as the role of ERVs in tumor development. Citation Format: Jieyu Zhang, Savannah Higgins, Riley Smith, Tania Reginald, Andrew Qi, Jiayi Li, Anna King, Yingguang Liu. Inhibition of murine tumor growth by decitabine is correlated with enhanced expression of the mouse mammary tumor virus. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4899.
Abstract 3755: <i>Dlx4os</i>: a lncRNA associated with malignant melanocyte transformation
Authors: Ana Luísa P. Ayub, Hatylas Azevedo, Diogo Pessoa, Leinal Sejour, Ioannis Vlachos, Eduardo M. Reis, Frank J. Slack, Miriam G. Jasiulionis
Journal: Cancer Research (2023)

Abstract It is estimated that more than 90% of the human genome is transcribed into non-coding RNAs (ncRNA). It has been demonstrated that ncRNAs have an important role in biological processes such as proliferation, differentiation, and cell migration. Changes in their expression have been associated with several diseases, including cancer. Melanoma is one of the most aggressive types of cancer, with high probability of metastasis and an unfavorable response to therapies. Our lab has developed an in vitro melanoma progression model, which was established by exposing nontumorigenic melanocytes (melan-a) to sustained stress conditions (cycles of adhesion blockage), sequentially generating different cell lines (i.e., 4C, premalignant melanocytes; 4C11-, non-metastatic melanoma cells; and 4C11+, metastatic melanoma cells), in which each cell line represents a distinct stage of tumor progression. Previous RNA sequencing data comparing these 4 cell lines identified a total of 3404 long non-coding transcripts which displayed differential expression (DE) levels when comparing two or more cell lines. We have clustered 531 of them into three distinct signatures: malignancy, epithelial-to-mesenchymal transition (EMT), or metastasis, according to their expression profiles. We also analyzed the neighboring genes of those lncRNAs, as it is known that lncRNAs might regulate gene expression in cis. We identified the lncRNA Dlx4os, highly expressed in undifferentiated and mesenchymal-like 4C and 4C11- cells, and 6 neighboring genes whose expression correlate to the EMT signature and overall survival in human melanoma patients. Among these genes we found Dlx4, which shares the same promoter site with Dlx4os and whose expression correlates to a poor prognosis. We silenced Dlx4os in the 4C11- cells through interference RNA technology. The downregulation of Dlx4os led to expression changes in EMT-related genes, such as Snail1, Sox10 and Mitf, indicating that it might play a role in EMT. Dlx4os downregulation also inhibited cell migration in vitro and tumorigenesis in vivo. These results overall indicate a role of Dlx4os in melanocyte malignant transformation. Citation Format: Ana Luísa P. Ayub, Hatylas Azevedo, Diogo Pessoa, Leinal Sejour, Ioannis Vlachos, Eduardo M. Reis, Frank J. Slack, Miriam G. Jasiulionis. Dlx4os: a lncRNA associated with malignant melanocyte transformation. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3755.
Abstract 3763: microRNAs associated with metastatic potential in salivary gland mucoepidermoid carcinoma
Authors: Maria Eduarda S. Trevizani, Katia K. Oliveira, Fabio A. Marchi, Daniela Bizinelli, Fernanda V. Mariano, Cibele P. Nagano, Felipe A. Costa, Clóvis A. Pinto, Luiz P. Kowalski, Silvia V. Lourenço, Cláudia M. Coutinho-Camillo
Journal: Cancer Research (2023)

Abstract Mucoepidermoid carcinoma (MEC) is the most common malignant tumor of the salivary glands. Metastatic spread occurs in up to 80% of high-grade tumors and it is a strong predictor of poor outcome, however, the mechanisms underlying this process are largely unknown. Large-scale microRNA expression profiling studies of human cancers have demonstrated that dysregulation of miRNA is frequently associated with many cancer types. The aim of this study was to investigate the microRNA profile in metastatic versus non-metastatic MECs. Using Real Time RT-PCR (qPCR) we have analyzed the expression of 384 miRNAs and controls in 4 non-metastatic MECs, 3 MECs with lymph node metastasis, 3 MECs with distant metastasis, and 2 non-neoplastic human salivary gland samples. The microRNA profile was able to discriminate between non-neoplastic and tumor samples and between metastatic and non-metastatic tumors. Considering non-neoplastic samples and non-metastatic MECs, 12 microRNAs were differentially expressed. The non-neoplastic versus lymph node metastasis MEC analysis demonstrated that 10 microRNAs were differentially expressed. Considering non-neoplastic versus distant metastasis MECs, 3 microRNAs were differentially expressed: 1 down-regulated and 2 up-regulated. Comparing non-metastatic MECs versus lymph node metastasis MECs we observed 17 up-regulated microRNAs. Considering non-metastatic MECs versus distant metastasis MECs, 2 microRNAs were up-regulated. One microRNA is differentially expressed between lymph node metastasis MECs and distant metastasis MECs. Our results suggest that microRNA profiles could discriminate the metastatic potential of salivary MECs and might be helpful in diagnostic and prognostic evaluation of patients. Citation Format: Maria Eduarda S. Trevizani, Katia K. Oliveira, Fabio A. Marchi, Daniela Bizinelli, Fernanda V. Mariano, Cibele P. Nagano, Felipe A. Costa, Clóvis A. Pinto, Luiz P. Kowalski, Silvia V. Lourenço, Cláudia M. Coutinho-Camillo. microRNAs associated with metastatic potential in salivary gland mucoepidermoid carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3763.
Abstract 3749: Oncogenic role of Epstein-Barr virus lnc-BARTs in EBV associated tumors
Authors: LIU JIAYAN, Bobo Wing-Yee Mok, Songtao He, Honglin Chen
Journal: Cancer Research (2023)

Abstract While majority of humans infected with Epstein-Barr virus (EBV) is asymptomatic for whole life, EBV is found to associate with several human cancers, including Burkitt’s lymphoma, Hodgkin’s diseases, post-transplant lymphoproliferative disorder (PTLD), nasopharyngeal carcinoma (NPC) and gastric carcinoma. Among these EBV associated tumors, EBV genome is found in 100% of NPC tumor cells. EBV establishes a latent infection in NPC cells, expressing few viral proteins, but elevated levels of non-coding RNAs transcribed from the BamHI-A region of the EBV genome, designated BamHI-A rightward transcripts (BARTs). The family of EBV BART RNAs comprises BART-microRNAs (miRNAs) and long non-coding RNAs (lnc-BARTs). While versatile functions of BART miRNAs have been revealed, little is known about the role of EBV lnc-BARTs. Here, we provided evidence to show that BARTs mRNA which derived from multiple exons of BART function as regulatory long non-coding RNA, namely lnc-BARTs, in modulating the core network for maintaining EBV latency and promoting NPC oncogenesis through epigenetic mechanisms. Our results showed that the apoptosis rate of NPC cell lines with knockdown of EBV lnc-BARTs was significantly increased, suggesting that lnc-BARTs have an anti-apoptotic effect in EBV associated tumors. MS analysis was performed to identify host factors which interact with EBV lnc-BARTs in NPC cells. Lnc-BARTs were shown to directly interact with several transcriptional regulators, including BRD4 and SC35. Notably, RNA-FISH assays demonstrated that lnc-BARTs co-localize with BRD4 and SC35 complexes in nuclear speckles, with these complexes being disrupted by treatment with JQ1, a BRD4 competitive inhibitor. RNA immunoprecipitation and RNA pulldown assays confirmed that lnc-BARTs bind to BRD4. ATAC sequencing analysis and transcriptome analysis further demonstrated that knockdown of BARTs in the EBV-harboring NPC cell line, C666-1, resulted in globally reduced chromatin accessibility downregulation of oncogenes like MYC and BCL2. In addition, ChIP sequencing analysis revealed that lnc-BARTs interfere PolII phosphorylation on promoters of genes. Our findings suggest that EBV lnc-BARTs are involved in epigenetic modulation of host gene expression through functional interaction with elongation regulatory machinery to maintain EBV latency and drive tumorigenesis in NPC. Citation Format: LIU JIAYAN, Bobo Wing-Yee Mok, Songtao He, Honglin Chen. Oncogenic role of Epstein-Barr virus lnc-BARTs in EBV associated tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3749.
Abstract 2235: A treatment for glioblastoma with a novel epigenetic inhibitor and identification of its target
Authors: Tokunaga Kota
Journal: Cancer Research (2023)

Abstract Glioblastoma multiforme (GBM) is one of the deadliest human cancers. Despite extensive efforts to develop a new treatment, the prognoses of patients have not changed dramatically over the past several decades. LSD1 plays an essential role in the epigenetic regulation of gene expression in many cancer cells, including GBM, as it removes methyl groups from histone H3 lysine (K) 4me1/2 and H3K9me1/2. Since it was reported that suppression of LSD1 induced apoptosis of glioblastoma stem cells (GSCs), LSD1 has been expected as an effective therapeutic target for GBMs, particularly enriched with GSCs. We newly discovered an LSD inhibitor (S2172) that suppressed the LSD1 enzymatic activity effectively and sufficiently penetrated into brain. We found that S2172 showed a strong inhibitory effect on cell growth not only in GCS cells but also in differentiated GBM cells in vitro. In GBM cell line U251, IC50 of S2172 was lower than that of other LSD1 inhibitors (IC50 10.5 μM, 29.5 μM, 11.0 μM treated with S2172, Ory-1001, and CC-90011, respectively). We also found a robust suppression of transcription of oncogene Myc in differentiated GBM cells after S2172 treatment, which is highly expressed in most GBM cells and considered as a key element to maintain its stemness and proliferation. Consistent with the expression analysis, chromatin immunoprecipitation-sequencing (ChIP-seq) revealed that enrichment of H3K4m2 and H3K4m3 was efficiently altered by S2172 treatment along with the change of Myc expression. Finally, we treated U251 brain tumor mouse model with S2172. While S2172 had a strong effect in vitro, S2172 seemed unsuccessful in killing differentiated GBM cells in vivo. These data suggests that treatment of S2172 is less effective to differentiated GBM cells and this is consistent with previous report that LSD1 as a candidate therapeutic target in stem-like tumor propagating cells in GBM. Citation Format: Tokunaga Kota. A treatment for glioblastoma with a novel epigenetic inhibitor and identification of its target [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2235.
Abstract 3820: Changes in the transcriptome of a triple negative breast cancer cell line following treatment with a water-soluble extract from the leaves of the indigenous Southern African plant <i>Tulbaghia violacea</i>
Authors: Zodwa Dlamini, Rodney Hull, Mohammed Alouna, Clement Penny
Journal: Cancer Research (2023)

Abstract Triple negative breast cancer (TNBC) accounts for approximately 20% of all breast cancer cases. And is defined by the absence of oestrogen, progesterone, and human epidermal growth factor 2 receptors. This makes it difficult to treat and leads to a low five-year survival rate. In South Africa a large percentage of the population still relies on traditional medicine based on the use of medicinal plants. One of these plants, African garlic (Tulbaghia violacea), that has been used to treat symptoms similar to that observed in cancer. However, the usefulness of these treatments has yet to be clinically proven. Previous studies have revealed that the water-soluble extract from the leaves of T. violacea had anticancer activity against a TNBC cell line. In order to identify the signalling pathways involved in this anti-cancer activity whole transcriptome sequencing was performed using RNA extracted from both TNBC and normal breast cells before and after treatment with the water-soluble T. violacea extract. Paired end sequencing was performed at a depth of 10 million bases for 300 cycles. Data analysis was performed using the Galaxy platform/Sequencing results led us to perform an antibody array assay for proteins involved in the receptor tyrosine kinase pathway. In line with the increased levels of apoptosis previously observed following treatment of the TNBC cell line with the extract, there was an increase in the transcription of genes associated with apoptosis. Decreases were observed in the transcription of genes involved in growth receptor signalling, angiogenesis, and cancer related pathways such as the Wnt, Notch and the PI3K pathway. This work highlights the pathways affected by compounds present within a water-soluble extract of the leaves of T, violacea. Combined with the results of our [previous work, this indicates that the compounds isolated from T, violacea could serve as lead compounds for the development of future therapeutic treatments for TNBC. Citation Format: Zodwa Dlamini, Rodney Hull, Mohammed Alouna, Clement Penny. Changes in the transcriptome of a triple negative breast cancer cell line following treatment with a water-soluble extract from the leaves of the indigenous Southern African plant Tulbaghia violacea. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3820.